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CD36 mediates lipid accumulation in pancreatic beta cells under the duress of glucolipotoxic conditions: Novel roles of lysine deacetylases.

ABSTRACT: The cluster of differentiation 36 (CD36) is implicated in the intake of long-chain fatty acids and fat storage in various cell types including the pancreatic beta cell, thus contributing to the pathogenesis of metabolic stress and diabetes. Recent evidence indicates that CD36 undergoes post-translational modifications such as acetylation-deacetylation. However, putative roles of such modifications in its functional activation and onset of beta cell dysregulation under the duress of glucolipotoxicity (GLT) remain largely unknown. Using pharmacological approaches, we validated, herein, the hypothesis that acetylation-deacetylation signaling steps are involved in CD36-mediated lipid accumulation and downstream apoptotic signaling in pancreatic beta (INS-1832/13) cells under GLT. Exposure of these cells to GLT resulted in significant lipid accumulation without affecting the CD36 expression. Sulfo-n-succinimidyl oleate (SSO), an irreversible inhibitor of CD36, significantly attenuated lipid accumulation under GLT conditions, thus implicating CD36 in this metabolic step. Furthermore, trichostatin A (TSA) or valproic acid (VPA), known inhibitors of lysine deacetylases, markedly suppressed GLT-associated lipid accumulation with no discernible effects on CD36 expression. Lastly, SSO or TSA prevented caspase 3 activation in INS-1832/13?cells exposed to GLT conditions. Based on these findings, we conclude that an acetylation-deacetylation signaling step might regulate CD36 functional activity and subsequent lipid accumulation and caspase 3 activation in pancreatic beta cells exposed to GLT conditions. Identification of specific lysine deacetylases that control CD36 function should provide novel clues for the prevention of beta-cell dysfunction under GLT.

SUBMITTER: Khan S

PROVIDER: S-EPMC5756509 | biostudies-literature | 2018 Jan

REPOSITORIES: biostudies-literature

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CD36 mediates lipid accumulation in pancreatic beta cells under the duress of glucolipotoxic conditions: Novel roles of lysine deacetylases.

Khan Sabbir S Kowluru Anjaneyulu A

Biochemical and biophysical research communications 20171220 3

The cluster of differentiation 36 (CD36) is implicated in the intake of long-chain fatty acids and fat storage in various cell types including the pancreatic beta cell, thus contributing to the pathogenesis of metabolic stress and diabetes. Recent evidence indicates that CD36 undergoes post-translational modifications such as acetylation-deacetylation. However, putative roles of such modifications in its functional activation and onset of beta cell dysregulation under the duress of glucolipotoxi ...[more]

PMID: 29274335

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Project description:Due to an increasing problem of drug resistance among almost all parasites species ranging from protists to worms, there is an urgent need to explore new drug targets and their inhibitors to provide new and effective parasitic therapeutics. In this regard, there is growing interest in exploring known drug leads of human epigenetic enzymes as potential starting points to develop novel treatments for parasitic diseases. This approach of repurposing (starting with validated targets and inhibitors) is quite attractive since it has the potential to reduce the expense of drug development and accelerate the process of developing novel drug candidates for parasite control. Lysine deacetylases (KDACs) are among the most studied epigenetic drug targets of humans, and a broad range of small-molecule inhibitors for these enzymes have been reported. In this work, we identify the KDAC protein families in representative species across important classes of parasites, screen a compound library of 23 hydroxamate- or benzamide-based small molecules KDAC inhibitors, and report their activities against a range of parasitic species, including the pathogen of malaria (Plasmodium falciparum), kinetoplastids (Trypanosoma brucei and Leishmania donovani), and nematodes (Brugia malayi, Dirofilaria immitis and Haemonchus contortus). Compound activity against parasites is compared to that observed against the mammalian cell line (L929 mouse fibroblast) in order to determine potential parasite-versus-host selectivity). The compounds showed nanomolar to sub-nanomolar potency against various parasites, and some selectivity was observed within the small panel of compounds tested. The possible binding modes of the active compounds at the different protein target sites within different species were explored by docking to homology models to help guide the discovery of more selective, parasite-specific inhibitors. This current work supports previous studies that explored the use of KDAC inhibitors in targeting Plasmodium to develop new anti-malarial treatments, and also pioneers experiments with these KDAC inhibitors as potential new anthelminthics. The selectivity observed begins to address the challenges of targeting specific parasitic diseases while limiting host toxicity.

Dataset Information

CD36 mediates lipid accumulation in pancreatic beta cells under the duress of glucolipotoxic conditions: Novel roles of lysine deacetylases.

Publications

CD36 mediates lipid accumulation in pancreatic beta cells under the duress of glucolipotoxic conditions: Novel roles of lysine deacetylases.

Similar Datasets

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